Gut Receptor Loss Lets Fungus Worsen Neutrophilic Allergic Airway Disease in Mice

A study in mice published in Nature Communications reports that deficiency of the aryl hydrocarbon receptor (AhR) in gut epithelial cells aggravates house dust mite–induced allergic airway disease when the commensal fungus Candida albicans colonizes the intestine orally. The work, by Ting Wang, Chao Lei, and colleagues, traces this worsening to a remote signaling axis that links intestinal AhR, IL-17 responsiveness, gut microbial composition, and glycosylation of lung structural cells, ultimately driving neutrophilic inflammation in the airways.

Fungal and bacterial dysbiosis have previously been associated with asthma severity, but how overgrowth of C. albicans contributes to disease progression remained incompletely understood. In the new experiments, intestinal AhR deficiency promoted exaggerated IL-17 responses, which increased neutrophil migration and accumulation in the lung and simultaneously reshaped the gut microbiota.

A particularly notable microbial change was a reduction in the abundance of Akkermansia muciniphila, a commensal bacterial species. This shift occurred alongside the intensified IL-17 signaling, placing the gut community composition directly within the pathway connecting the missing epithelial receptor to lung inflammation.

The researchers also identified a glycan-based mechanism governing neutrophil behavior in inflamed lung tissue. Loss of intestinal AhR increased fucosylation of lung structural cells, which enhanced the biosynthesis of glycan ligands for L-selectin, an adhesion molecule carried by neutrophils. This glycosylation change promoted neutrophil adhesion and retention within the lung. The adherent neutrophils were associated with mitochondrial dysfunction, oxidative stress, and tissue injury in both epithelial and endothelial compartments of the lung.

The study then tested whether the pathway could be interrupted. Administration of A. muciniphila or its derived outer membrane vesicles (OMVs) reduced lung fucosylation, suppressed neutrophil adhesion and neutrophil extracellular trap (NET) formation, and attenuated the Candida albicans–exacerbated allergic airway disease. Genetic deletion of Fut2, the fucosyltransferase gene required for synthesizing the L-selectin glycan ligands, produced comparable effects, reducing fucosylation and neutrophil retention and easing airway inflammation.

Together, the findings indicate that intestinal AhR signaling remotely regulates an IL-17–gut microbiota–fucosylation axis that promotes neutrophil adhesion, mitochondrial dysfunction of lung structural cells, and neutrophilic airway inflammation during Candida albicans–associated asthma in mice. The authors propose that this axis explains how overgrowth of a common commensal fungus can worsen allergic airway disease when a key gut epithelial sensor is missing.

Several caveats frame the significance of the results. All experiments were performed in mouse models of house dust mite–induced allergic airway disease with controlled oral Candida albicans colonization, so the findings are measured observations in animals rather than demonstrations of clinical benefit in humans. The reported relationships between AhR deficiency, fungal overgrowth, microbial abundance, and lung fucosylation were established under these controlled laboratory conditions and have not yet been verified in human subjects.

Within those limits, the study offers a mechanistic account of how gut epithelial AhR deficiency, fungal dysbiosis, and lung glycosylation converge on neutrophilic airway disease. It also identifies candidate intervention points along the axis: restoring A. muciniphila abundance or its OMVs, or blocking Fut2-dependent fucosylation, each reduced neutrophil adhesion and NET formation and attenuated disease in the mouse model. Whether comparable AhR, microbiota, and fucosylation relationships operate in human asthma, and whether A. muciniphila-derived vesicles could be developed as therapies, remain questions for future research beyond the scope of the current mouse experiments.

Subject of Research: Gut epithelial aryl hydrocarbon receptor deficiency aggravates fungal dysbiosis-mediated neutrophilic allergic airway disease in mice

Article Title: Gut epithelial aryl hydrocarbon receptor deficiency aggravates fungal dysbiosis-mediated neutrophilic allergic airway disease in mice

Article References: Wang, T., Lei, C., Xu, Z., Song, X., Tuohongerbieke, A., Jones, T., Kong, M., Hao, C., Chen, Z., Tan, Y., Yan, J., McClain, C. J., & Deng, Z. (2026). Gut epithelial aryl hydrocarbon receptor deficiency aggravates fungal dysbiosis-mediated neutrophilic allergic airway disease in mice. Nature Communications. https://doi.org/10.1038/s41467-026-78800-6

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78800-6

Keywords: epithelial, aryl, hydrocarbon, receptor, deficiency, aggravates, fungal, dysbiosis-mediated, neutrophilic, allergic, airway, disease